G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha 1B-adrenergic receptor enhances mitogenesis and tumorigenicity.
Abstract
The alpha 1B-adrenergic receptor (alpha 1B-ADR) is a member of the G-protein-coupled
family of transmembrane receptors. When transfected into Rat-1 and NIH 3T3 fibroblasts,
this receptor induces focus formation in an agonist-dependent manner. Focus-derived,
transformed fibroblasts exhibit high levels of functional alpha 1B-ADR expression,
demonstrate a catecholamine-induced enhancement in the rate of cellular proliferation,
and are tumorigenic when injected into nude mice. Induction of neoplastic transformation
by the alpha 1B-ADR, therefore, identifies this normal cellular gene as a protooncogene.
Mutational alteration of this receptor can lead to activation of this protooncogene,
resulting in an enhanced ability of agonist to induce focus formation with a decreased
latency and quantitative increase in transformed foci. In contrast to cells expressing
the wild-type alpha 1B-ADR, focus formation in "oncomutant"-expressing cell lines
appears constitutively activated with the generation of foci in unstimulated cells.
Further, these cell lines exhibit near-maximal rates of proliferation even in the
absence of catecholamine supplementation. They also demonstrate an enhanced ability
for tumor generation in nude mice with a decreased period of latency compared with
cells expressing the wild-type receptor. Thus, the alpha 1B-ADR gene can, when overexpressed
and activated, function as an oncogene inducing neoplastic transformation. Mutational
alteration of this receptor gene can result in the activation of this protooncogene,
enhancing its oncogenic potential. These findings suggest that analogous spontaneously
occurring mutations in this class of receptor proteins could play a key role in the
induction or progression of neoplastic transformation and atherosclerosis.
Type
Journal articleSubject
Amino Acid SequenceAnimals
Cell Division
Cell Line
Cell Membrane
Cell Transformation, Neoplastic
Cricetinae
GTP-Binding Proteins
Genes, ras
Inositol Phosphates
Kinetics
Mice
Mice, Nude
Molecular Sequence Data
Neoplasm Transplantation
Plasmids
Protein Conformation
Proto-Oncogenes
Rats
Receptors, Adrenergic, beta
Transfection
Transplantation, Heterologous
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Show full item recordScholars@Duke
Marc G. Caron
James B. Duke Distinguished Professor of Cell Biology
Studies of the mechanisms of action and regulation of hormones and neurotransmitters
at the cellular and molecular levels constitute the main goals our of research activities.
G protein-coupled receptors (GPCR) mediate the actions of signaling molecules from
unicellular organisms to man. We have used adrenergic and dopamine receptors to characterize
the structure/function and regulation mechanisms of these prototypes of G protein-coupled
receptors. Another approach has been to characterize
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his
early career as a cardiologist and his transition to biochemistry, which led to his
Nobel Prize win.
Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of
Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator
of the
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